Do clinical features of Lesch-Nyhan disease correlate more closely with hypoxanthine or guanine recycling?
Do clinical features of Lesch-Nyhan disease correlate more closely with hypoxanthine or guanine recycling?
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DOI：
10.1007/s10545-015-9869-x
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发表时间：
2016-01
影响因子：
4.2
通讯作者：
Jinnah HA
中科院分区：
文献类型：
--
作者：
Schretlen DJ;Callon W;Ward RE;Fu R;Ho T;Gordon B;Harris JC;Jinnah HA
莱-尼二氏病（LND）是一种罕见的X连锁隐性遗传性神经发育障碍，由次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGprt）缺乏引起，HGprt是嘌呤补救途径中的一种酶。HGprt有两个功能：它能分解次黄嘌呤和鸟嘌呤。这两种功能中哪一种与发病机制更相关尚不清楚，因为一些证据表明次黄嘌呤循环，但其他证据表明鸟嘌呤循环。在这项研究中，我们选择性地测定了次黄嘌呤（Hprt）和鸟嘌呤（Gprt）的皮肤成纤维细胞从17人LND，11与减毒变异的疾病（LNV），和19个年龄，性别和种族匹配的健康对照（HC）的再循环。两种酶的活性水平在各组之间存在差异（p< 0.0001），但只有Gprt将LND患者与LNV患者区分开来（p<0.05）。GPRT与14项临床表型指标中的13项指标的相关性也略强于Hprt，这些指标包括肌张力障碍的严重程度、认知障碍和行为异常。这些发现表明，鸟嘌呤再循环的损失可能比次黄嘌呤再循环的损失与LND/LNV表型更密切相关。
Lesch-Nyhan disease (LND) is a rare, X-linked recessive neurodevelopmental disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme in the purine salvage pathway. HGprt has two functions; it recycles hypoxanthine and guanine. Which of these two functions is more relevant for pathogenesis is unclear because some evidence points to hypoxanthine recycling, but other evidence points to guanine recycling. In this study, we selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with LND, 11 with an attenuated variant of the disease (LNV), and 19 age-, sex-, and race-matched healthy controls (HC). Activity levels of both enzymes differed across groups (p< 0.0001), but only Gprt distinguished patients with LND from those with LNV (p<0.05). Gprt also showed slightly stronger correlations than Hprt with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These findings suggest that loss of guanine recycling might be more closely linked to the LND/LNV phenotype than loss of hypoxanthine recycling.
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影响因子：
4.2
作者：
PAGE, T;BAKAY, B;NYHAN, WL
通讯作者：
NYHAN, WL
影响因子：
4.7
作者：
Göttle M;Burhenne H;Sutcliffe D;Jinnah HA
通讯作者：
Jinnah HA
影响因子：
4.2
作者：
MATEOS, FA;PUIG, JG
通讯作者：
PUIG, JG
影响因子：
4.7
作者：
Shirley, Thomas L.;Lewers, J. Chris;Jinnah, H. A.
通讯作者：
Jinnah, H. A.
影响因子：
14.9
作者：
Shriner D;Baye TM;Padilla MA;Zhang S;Vaughan LK;Loraine AE
通讯作者：
Loraine AE